Method of treating urinary bladder dysfunctions

ABSTRACT

The present invention relates to a novel method for treating a mammal suffering from urinary bladder dysfunctions.

This is a divisional application of application Ser. No. 08/336,357,filed Nov. 8, 1994 now U.S. Pat. No. 5,612,351, the contents of whichare incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention provides a novel method using cholinergic agonistsfor treatment of sensory abnormalities of the bladder such as urgeincontinence, urinary frequency, urgency, nocturia and interstitialcystitis, or contractile dysfunction.

The function of the lower urinary tract is storage and periodic releaseof urine. Inability to store urine is called urinary incontinence. Thereare two clinically-recognized forms of incontinence, stress incontinenceand urge incontinence. Stress incontinence is defined as a loss of urinewhich results from urethral sphincter insufficiency during periods ofelevated abdominal pressure (i.e. stress), while urge incontinence isdue to bladder smooth muscle hyperactivity which is accompanied byfeelings of urgency to urinate. Bladder hyperactivity, without loss ofurine, can also lead to urinary frequency, urgency, and nocturia, whichare also clinically significant problems for a large patient population.Urgency may also be accompanied by pelvic pain, which arises from thebladder. This condition is termed interstitial cystitis. Bladderhyperreflexia, urgency, and interstitial cystitis are dependent upon thesensory innervation of the bladder, particularly those sensations whichare perceived as noxious.

Currently prescribed medicines, which include muscarinic cholinergicantagonists (i.e. anti-cholinergics such as oxybutynin) or spasmolytics(such as flavoxate), suppress bladder contractions by effecting theefferent or motor component of micturition, but which have no effect orexacerbate the sensory components of bladder dysfunction. By suppressingthe ability of the bladder to contract, these compounds prevent thebladder from completely emptying and thus produce significant residualurine, which is conducive to the formation of bladder infection.Furthermore, since these drugs do not effect the sensory limb of bladderfunction, they are not effective for conditions such as interstitialcystitis. Often, these latter patients must resort to removal of thebladder for treatment of their bladder pain. Thus, we believe that adrug that suppresses the ability of the bladder to contract and reducesnoxious sensory input from the bladder would be useful for treatingbladder dysfunctions.

We have discovered a new class of muscarinic agents which have notpreviously been considered for treating urinary bladder dysfunctions.

SUMMARY OF THE INVENTION

The method of this invention comprises administering to a patientsuffering from urinary bladder dysfunction an effective amount of acompound of the formula I ##STR1## wherein X is oxygen or sulphur;

R is hydrogen, amino, halogen, --CHO, --NO₂, --R⁴, --Y, --NHCO--R⁴,--OR⁴, --SR⁴, --SOR⁴, --SO₂ R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₀ -cycloalkenyl,C₄₋₁₀ -(cycloalkylalkyl) --Z¹ --C₃₋₁₀ -cycloalkyl, --Z¹ --C₄₋₁₀-cycloalkenyl, --Z¹ --C₄₋₁₀ -(cycloalkylalkyl), --Z--C₄₋₁₀-(cycloalkenylalkyl), --Z¹ --C₄₋₁₀ -(methylenecycloalkylalkyl),--NH--R⁴, --NR⁴ R⁵, --NH--OR⁴, --CH═NOR⁴, phenyl, benzyloxycarbonyl,phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indenyl, wherein eacharomatic group is optionally substituted with halogen, --NO₂, --CN,C₄₋₁₀ -alkyl, C₄₋₁₀ -alkoxy, --OCF₃, --CONH₂, --CSNH₂, phenoxy orphenyl; or R is --Z¹ --R⁶ --Z² --R⁵, --Z¹ --R⁶ --Z² --R⁷ --Z³ --R⁵, --Z¹--CO--R⁵, --Z¹ --R⁶ --CO--R⁵, --Z¹ --R^(6--CO) ₂ --R⁵, --Z¹ --R⁶ --O₂C--R⁵, --Z¹ --R⁶ --CONH--R⁵, --Z¹ --R⁶ --NHCO--R⁵, --Z--R⁶ --Y, --Z¹--R⁶ --Z² --Y, wherein Z¹ and Z² independently are oxygen or sulphur,and R⁴ and R⁵ independently are straight or branched C₁₋₁₅ -alkyl,straight or branched C₂₋₁₅ -alkenyl, straight or branched C₂₋₁₅-alkynyl, each of which is optionally substituted with one or morehalogen(s), C₁₋₆ -alkoxy, --CF₃, --CN, --COOH, --OH, --NH₂, C₁₋₆ -alkylester, --SH, --NHR⁴, --NR⁴ R⁵, phenyl or phenoxy, wherein each aromaticgroup is optionally substituted with halogen, --NO₂, --CN, C₁₋₄ -alkyl,C₁₋₄ -alkoxy, --OCF₃, --CONH₂, --CSNH₂, phenyl or phenoxy, and whereinR⁶ and R⁷ independently are straight or branched C₁₋₁₀ -alkylene,straight or branched C₂₋₁₀ -alkenylene, straight or branched C₂₋₁₀-alkynylene, each of which is optionally substituted with one or morehalogen(s), --CF₃, --CN, --COOH, --OH, --NH₂, C₁₋₆ -alkyl ester, --SH,--NHR⁴, --NR⁴ R⁵, phenyl or phenoxy, and Y is a 5 or 6 memberedheterocyclic group containing one to four N, O or S atom(s) or acombination thereof, which heterocyclic group is optionally substitutedat carbon or nitrogen atom(s) with straight or branched C₁₋₆ -alkyl,phenyl or benzyl, or a carbon atom in the heterocyclic group togetherwith an oxygen atom form a carbonyl group, or which heterocyclic groupis optionally fused with a phenyl group; and

G is selected from one of the following azabicyclic rings ##STR2##wherein the thiadiazole or oxadiazole ring can be attached at any carbonatom of the azabicyclic ring; R¹ and R² may be present at any position,including the point of attachment of the thiadiazole or oxadiazole ring,and independently are hydrogen, straight or branched C₁₋₅ -alkyl,straight or branched C₂₋₅ -alkenyl, straight or branched C₂₋₅ -alkynyl,straight or branched C₁₋₁₀ -alkoxy, straight or branched C₁₋₅ -alkylsubstituted with --OH, --OH, halogen, --NH₂ or carboxy; R³ is H,straight or branched C₁₋₅ -alkyl, straight or branched C₂₋₅ -alkenyl orstraight or branched C₂₋₅ -alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is0, 1 or 2; q is 1 or 2; and . . . is a single or double bond; or

a pharmaceutically acceptable salt thereof.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride; hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate, or similarpharmaceutically acceptable inorganic or organic acid addition salts,and include the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are hereby incorporated byreference.

Especially preferred salts include tartrate and hydrochloride.

As used herein, the term "patient" includes any mammal which couldbenefit from treatment of urinary bladder dysfunctions. The termparticularly refers to a human patient, but is not intended to be solimited.

The thiadiazole and oxadiazole compounds used in the presently claimedmethod have been disclosed and claimed in PCT/DK91/00236. Thethiadiazole and oxadiazole derivatives are known to be cholinergicmuscarinic agents useful in the treatment of presenile and seniledementia. The compounds are believed to be useful for treatingAlzheimer's disease, glaucoma, and painful conditions. Other disclosuressuggest that thiadiazole compounds may be useful for the treatment ofillnesses whose clinical manifestations are due to cholinergicdeficiency, (European Patent Application 307142). Such illnesses includeHuntington's chorea, tardive dyskinesia, hyperkinesia, mania, andTourette Syndrome.

The compounds of this method produce a dose-dependent inhibition ofvesico-anal reflex activity that is reversed by atropine, a centrallyactive muscarinic antagonist.

In addition, the compounds of this method have been found to have afavourable profile of activity in a number of in vitro binding assays,designed to measure the degree of binding to neural receptors.

The compounds have IC₅₀ levels of less than 1 μM in the ³H-oxotremorine-M binding assay, indicating that the compounds havemuscarinic receptor affinity.

This profile of activity in in vitro receptor binding assays, like thatobserved in the acetic acid-induced vesico-anal reflex test, wouldindicate that the compounds are effective in the treatment of urinarybladder dysfunctions.

Methods

The model of visceral nociception that was used in the testing of thecompounds according to the method of this invention is the aceticacid-induced vesico-anal reflex. This model utilizes infusion of adilute acetic acid solution into the urinary bladder as a nociceptivestimulus and records increases in electromyographic (EMG) activity fromthe anal sphincter as the primary measured response. Anal sphincter EMGactivity is composed of 2 components, 1) a small, long duration actionpotential (ca. 50 msec) that is sensitive to muscarinic antagonists and2) a larger, short duration action potential (ca. 2 msec) that issensitive to neuromuscular blocking agents (i.e. mediated by nicotinicreceptors). These components represent rectal longitudinal smooth muscleactivity and external anal sphincter striated muscle activity,respectively, and have been described in detail in a separatepublication (Muhlhauser reference). It is the striated anal sphinctermuscle activity that 1) is associated with bladder activity, 2) isincreased by acetic acid infusion into the bladder, and 3) representsthe vesico-anal reflex. The acetic acid-induced increase in vesico-analreflex activity is maintained for over 2 hours in 95% of the animals.

In the acetic acid-induced vesico-anal reflex model, bladders ofurethane-anesthetized rats were cannulated through the dome forcontinuous-infusion cystometrogram recordings. EMG electrodes wereinserted into the anus and the peri-urethral musculature for recordinganal and urethral sphincteric activity, respectively. Infusion of 0.5%acetic acid into the bladder or urethra produced modest increases inbladder contractile activity and urethral sphincter activity andpronounced increases in anal sphincter activity (i.e. an increase in thevesico-anal reflex). Oxotremorine (1-30 μg/kg iv), a centrally-activecholinergic agonist, and the test compounds (0.01-1.0 mg/kg iv) produceddose-dependent inhibition of vesico-anal reflex activity (to 10% ofcontrol) that was reversed by atropine (0.3-1 mg/kg), a centrally activemuscarinic antagonist. Scopolamine methyl bromide (1-30 ug/kg), aperipherally-restricted muscarinic antagonist, was ineffective atblocking the cholinergic agonist-mediated inhibition of the vesico-analreflex. This indicates that oxotremorine-induced inhibition of the VAreflex and that of the test compounds was centrally mediated.Furthermore, when atropine (30 μg/kg-1 mg/kg) and oxybutynin (1-3 mg/kg,a muscarinic antagonist used clinically for bladder dysfunction) wereadministered alone, robust, but transient (15 min.), increases invesico-anal reflex activity were recorded. This indicated thatendogenous acetylcholine was partially suppressing the vesico-analreflex via tonic muscarinic mechanisms. This indication was supported bythe finding that the centrally active cholinesterase inhibitor,physostigmine (but not the peripherally-restricted cholinesteraseinhibitor, neostigmine) also suppressed the VA reflex in adose-dependent, atropine-sensitive manner. These studies indicate that atonically-active, endogenous, cholinergic muscarinic system plays a rolein the suppression of visceral nociception arising from the lowerurinary tract.

Experimental

Female Sprague-Dawley rats (200-300 g) were anesthetized with 1.4 g/kgurethane (0.7 g administered i.p. and 0.7 g administered s.c.), whichwas supplemented with 1% isoflurane during surgery. The urinary bladderwas exposed through an abdominal incision and cannulated with PE60tubing attached to a 22 gauge needle that was inserted through the domeof the bladder. A purse-string suture (5-0 silk) through the bladderheld the needle in place. The cannula was connected to an infusion pump(Harvard Apparatus, Natick Mass.) and a pressure transducer (StathamGould, Cleveland, Ohio) through a 3 way stopcock to allow bladderfilling and pressure measurement, respectively. The abdominal incisionwas covered with plastic wrap. A small incision was made in the perineumto allow placement of EMG electrodes into the periurethral musculature.EMG electrodes were also placed into the muscular tissue of the anus.EMG electrodes were connected to preamplifiers (Grass P511, Quincey,Mass.) with low and high pass filters set at 10 and 3000 HZ. EMGpotentials were displayed on an oscilloscope (Gould 1602, Cleveland,Ohio) that was interfaced to a differential amplitude discriminator/ratemeter with wave-form discrimination capability (RAD III, WinstonElectronics, Millbrae, Calif.). A catheter inserted into the carotidartery was connected to a pressure transducer (Statham Gould, Cleveland,Ohio) to record arterial pressure, which was used to trigger a heartrate meter (Biotach, Gould, Cleveland, Ohio). A catheter was insertedinto the trachea to allow for artificial respiration and monitoring ofexpired CO₂ (Sensor Medics, Anaheim, Calif.). EMG potentials, rate meteroutput, bladder and arterial pressure, heart rate, and expired CO₂measurements were recorded on a physiograph (Gould, TA4000, Cleveland,Ohio) and stored on an 8-channel digital audio tape recorder (SONYPC-108M, Tokyo, Japan).

After establishing control levels of anal and urethral activity,compounds were administered intravenously. Oxotremorine sesquifumarate(Sigma Chemicals, St. Louis, Mo.), atropine sulfate (RBI, Natick, Mo.),(-) scopolamine methyl bromide (RBI), physostigmine free base (SigmaChemicals), neostigmine bromide (Sigma) and the test compounds were alldissolved in physiological saline.

The affinity of the compounds for the muscarinic receptors wasdetermined using the non-selective agonist ligand, ³ H-oxotremorine-M.Birdsdall N. J. M., Hulme E. C., and Burgen A. S. V., "The Character ofMuscarinic Receptors in Different Regions of the Rat Brain", 207 Proc.Roy. Soc. 1 (London, Series B, 1980). The results of this assay aredescribed in Table I below. Each compound was tested to determine theaffinity of the compound for the muscarinic receptors using thefollowing procedure.

For in vitro binding, male Sprague-Dawley (Harlan Sprague-Dawley,Indianapolis, Ind.) rats weighing from about 100 to about 150 grams eachwere sacrificed by decapitation. The brains were quickly removed and thecerebral cortex were dissected from the brain. The cerebral cortextissue was homogenized in 10 volumes of 0.32M sucrose and homogenizedfor about 10 minutes at about 1000×g. The supernatant was centrifuged atabout 12,000×g for about 10 minutes and the resulting pellet wasresuspended in 20 mM tris-Cl, pH 7.4. The resuspended pellet wascentrifuged again for about 10 minutes at about 50,000×g. The resultinghomogenate was preincubated for about 10 minutes at about 25° C. andcentrifuged again for about 10 minutes at about 50,000×g. The pellet wasresuspended at 1 gram of pellet per 3 ml of buffer and frozen at about-80° C. until used.

The inhibition of binding of ³ H-oxotremorine-M to muscarinic receptorswas determined by mixing the compound of the Example, 3 nM ³H-oxotremorine-M (about 87 Ci/mmoles, New England Nuclear, BostonMass.), and cerebral cortical membranes equivalent to about 10 mg wetweight, which is about 100 μg of cortical membrane protein, in about 1ml total volume of 20 nM tris-Cl buffer, pH 7.4, containing 1 mM MnCl₂.The aforementioned homogenates mixture was incubated for about 15minutes at about 25° C. and then the homogenates were filtered throughglass filters (Whatman, GF/C) with vacuum. The filters were washed 3times with about 2 ml of cold tris-Cl buffer, and placed inscintillation vials containing about 10 ml of scintillation fluid (ReadyProtein+, Beckman, Fullerton, Calif.). Radioactivity trapped on thefilters was determined by liquid scintillation spectrometry. Nonspecificbinding was determined using 1 μM atropine. The concentration ofcompound required to inhibit specific binding 50% (IC₅₀) was determinedusing standardized computer assisted calculations (DeLean, A. et al. Am.J. Physiol., 235, (1978)).

Test results obtained by testing some compounds of the present inventionwill appear from the following Table 1:

                  TABLE 1                                                         ______________________________________                                        Compound      Inhibition of                                                   No.           .sup.3 H-Oxo (nM)                                               ______________________________________                                        9             2.1                                                             46            1.6                                                             13            1.9                                                             52            1.8                                                             53            0.9                                                             19            1.2                                                             29            1.2                                                             30            0.4                                                             31            1.8                                                             32            1.3                                                             58            0.8                                                             59            1.0                                                             56            0.4                                                             74            1.4                                                             76            7.7                                                             77            2.7                                                             82            1.3                                                             133           1.3                                                             102           4.5                                                             103           2.7                                                             104           2.6                                                             131           2.8                                                             106           2.8                                                             107           1.0                                                             111           1.0                                                             112           0.6                                                             113           0.89                                                            114           0.45                                                            119           0.9                                                             120           0.9                                                             121           1.0                                                             122           2.1                                                             130           1.8                                                             157           10                                                              158           10                                                              167           0.76                                                            ______________________________________                                    

The compounds used in this method are effective over a wide dosagerange. For example, in the treatment of adult humans, dosages from about0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per daymay be used. A most preferable dosage is about 10 mg to about 70 mg perday. In choosing a regimen for patients suffering from urinary bladderdysfunctions it may frequently be necessary to begin with a dosage offrom about 30 to about 70 mg per day and when the condition is undercontrol to reduce the dosage as low as from about 1 to about 10 mg perday. The exact dosage will depend upon the mode of administration, formin which administered, the subject to be treated and the body weight ofthe subject to be treated, and the preference and experience of thephysician or veterinarian in charge.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal,subcutaneous, intravenous, intraurethral, intramuscular, intranasal oran ointment, the oral route being preferred.

Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable carrier. In making the compositions,conventional techniques for the preparation of pharmaceuticalcompositions may be used. For example, the active compound will usuallybe mixed with a carrier, or diluted by a carrier, or enclosed within acarrier which may be in the form of a ampoule, capsule, sachet, paper,or other container. When the carrier serves as a diluent, it may besolid, semi-solid, or liquid material which acts as a vehicle,excipient, or medium for the active compound. The active compound can beadsorbed on a granular solid container for example in a sachet. Someexamples of suitable carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethyl-cellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or coloring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

Generally, the compounds are dispensed in unit form comprising fromabout 1 to about 100 mg in a pharmaceutically acceptable carrier perunit dosage.

A typical tablet, appropriate for use in this method, may be prepared byconventional tabletting techniques and contains:

    ______________________________________                                        Active compound     5.0 mg                                                    Lactose             67.8 mg Ph. Eur.                                          Avicel ®        31.4 mg                                                   Amberlite ®     1.0 mg                                                    Magnesium stearate  0.25 mg Ph. Eur.                                          ______________________________________                                    

The compounds used in this method may be prepared by commonly knownchemical methods. Most of the compounds may be prepared using themethods taught in PCT/DK91/00236 which are hereby incorporated byreference. The following description is intended to illustrate possiblesynthetic routes for the preparation of the compounds utilized in thismethod.

The compounds may be prepared by

a) reacting a compound of formula II ##STR3## wherein G has the meaningdefined above, >.sup.... N is >--NH or; >═N and R⁶ is H, OH or O-alkyl,with S₂ Cl₂ to form a compound of formula III ##STR4## wherein G has themeaning defined above; subsequent displacement of Cl with an appropriatenucleophile gives a compound of formula I wherein X is S, or

b) dehydrating a compound of formula IV ##STR5## wherein G has themeaning defined above and R⁷ is alkyl, amino, halogen, alkoxy oralkylthio, to form a compound of formula V ##STR6## wherein G and R⁷have the meanings defined above, or c) when R⁷ in formula V is amino,the amino group can be substituted by chloro by known procedures, andsubsequent displacement of Cl with an appropriate nucleophile gives acompound of formula I wherein X is O, or

d) oxidizing a compound of formula VI ##STR7## wherein G, R⁴ and X havethe meanings defined above by standard procedures to form a compound offormula VII ##STR8## and subsequent displacement of --SO₂ --R⁴ with anappropriate nucleophile to form a compound of formula I.

It is to be understood that the invention extends to each of thestereoisomeric forms of the compounds of formula I as well as theracemates.

The following examples are included to more specifically describe thepreparation of the compounds used in the method of this invention. Theexamples are not intended to limit the present invention in any way andshould not be so construed.

EXAMPLE 1

A. Ethyl(1-azabicyclo 2.2.2!octan-3-ylidine)cyanoacetate

A solution of 3-quinuclidone (75 g, 0.6 mol), ammonium acetate (2.3 g,30 mmol), acetic acid (3.75 ml) and ethyl cyanoacetate (67.8 g, 0.6 mol)in toluene (400 ml) was refluxed with a water separator for 18 h. Water(100 ml) and NaOH was added, and the mixture extracted several timeswith ether. The organic phases were dried and evaporated. The residuewas purified by column chromatography (eluent: EtOAc/MeOH (2:1)),yielding 73 g of the title compound.

B. Ethyl(1-azabicyclo 2.2.2!octan-3-yl)cyanoacetate

A solution of ethyl(1-azabicyclo 2.2.2!octan-3-ylidene)cyanoacetate (73g, 0.33 mol) in absolute ethanol (1 l) was treated with 10% palladium oncharcoal (10 g) and hydrogen in a parr shaker at 20 psi for 5 h.Filtration and evaporation gave the wanted product in 68 g yield.

C. (1-Azabicyclo 2.2.2!octan-3-yl)hydroxyiminoacetonitrile

Ethyl(1-azabicyclo 2.2.2!octan-3-yl)cyanoacetate (10 g, 45 mmol) wasadded to a solution of sodium (1.04 g, 45 mmol) in absolute ethanol (60ml). The mixture was stirred for 15 min. at room temperature andisoamylnitrite (7.9 ml, 60 mmol) was added. The reaction mixture wasstirred for 18 h at 60° C. Evaporation of the reaction mixture gavecrude title compound, which was used without further purification.

D. 3-Chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate

To a solution of crude (1-azabicyclo2.2.2!octan-3-yl)hydroxyiminoacetonitrile (max. 45 mmol) in DMF (60 ml)was slowly added a solution of S₂ Cl₂ (10.85 ml, 135 mmol) in DMF (20ml) at 0° C. After addition the reaction mixture was stirred at roomtemperature for 48 h. Water and 50% NaOH was added to the ice cooledreaction mixture and extracted with ether. The combined ether phaseswere dried and evaporated. The residue was purified by columnchromatography (eluent: EtOAc/MeOH (2:1)) to give the free base of thetitle compound in 1.04 g yield. Crystallization with oxalic acid fromacetone gave an analytical pure product (Compound 1). M.p. 137°-139° C.

EXAMPLE 2 3-(3-Chloro-1,2,5-thiadiazol-4-yl)-3-hydroxy-1-azabicyclo2.2.2!octane oxalate

A solution of 3-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (250 mg, 0.95 mmol) in ethanol (25 ml) was treated withformic acid (750 μl, 20 mmol), triethylamine (4.2 ml, 30 mmol) and 10%palladium on charcoal for 18 h at 60° C. After filtration andevaporation water and K₂ CO₃ was added to the residue and extracted withether. The dried ether phases were evaporated and purified by columnchromatography (eluent: EtOAc/MeOH (2:1)). Crystallization as theoxalate from acetone gave the title compound in 150 mg yield. (Compound2). M.p. 241°-242° C.

EXAMPLE 3 3-Methoxy-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate and3-(3-Methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!oct-2-ene oxalate

A solution of 3-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (500 mg, 1.9 mmol) and sodiummethoxide (20 mmol) inmethanol(20 ml) was stirred for 48 h at 60° C. Water was added to thereaction mixture and extracted with ether. The combined organic phaseswere dried and evaporated. The two products were separated by columnchromatography (eluent: EtOAc/MeOH (2:1)). Crystallization of thedimethoxy product as the oxalate from acetone gave 200 mg. (Compound 3).M.p. 113°-117° C. The monomethoxy oxalate was isolated in 60 mg yield(Compound 4). M.p. 143°-145° C.

EXAMPLE 4 3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!oct-2-ene oxalate,3-Hexyloxy-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate and3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-3-hydroxy-1-azabicyclo 2.2.2!octaneoxalate

A 50% sodiumhydride dispersion (960 mg, 20 mmol) was dissolved in1-hexanol and 3-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (500 mg, 1.9 mmol) was added. The reaction mixture wasstirred at 90° C. for 18 h and evaporated. The residue was dissolved inwater and extracted with ether. The dried ether phases were evaporatedand the products separated by column chromatography (eluent: EtOAc/MeOH(2:1)). The first fractions contained the eliminated product which,after crystallization with oxalic acid, was collected in 70 mg yield.(Compound 5). M.p. 135°-137° C.

The next fractions contained the dihexyloxy analogue, which gave 70 mgas the oxalate salt. (Compound 6). M.p. 84°-85° C.

The later fractions gave the hydroxy-hexyloxy compound in 100 mg yieldas the oxalate salt. (Compound 7). M.p. 145°-147° C.

EXAMPLE 5 3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate

Hydrogenation for 48 h of3-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane(15.2 g, 66 mmol) in ethanol (500 ml) at 30 psi in the presence of 10%palladium on charcoal (2.0 g) gave, after filtration and evaporation,the hydrochloride salt of the wanted product in quantitative yield.Crystallization of a sample with oxalic acid from methanol/acetone/etherproduced the title compound. (Compound 8). M.p. 207°-209° C.

EXAMPLE 6 3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate

Sodium (200 mg, 8.7 mmol) was dissolved in ethanol (30 ml) and3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane (300 mg,1.3 mmol) was added. The reaction mixture was stirred at 60° C. for 18h. Water was added and the reaction mixture extracted with ether. Thedried and filtrated ether extracts were evaporated to give the freebase. Crystallization as the fumarate salt from isopropanol/ether gavethe title compound in 210 mg yield. (Compound 9). M.p. 128°-131° C.

EXAMPLE 7

The following compounds were made in exactly the same manner asdescribed in example 6 using the appropriate alcohol:

3-(3-Propoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane fumarate.(Compound 10). M.p. 64°-67° C.

3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane oxalate.(Compound 46). M.p. 159°-160° C.

EXAMPLE 8 3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate

A 50% dispersion of sodiumhydride (230 mg, 5 mmol) was dissolved in1-hexanol (25 ml) and 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (250 mg, 1.1 mmol) was added. The reaction was stirred at80° C. for 8 h and at room temperature for 18 h. After evaporation waterwas added to the residue and extracted with ether. The combined etherphases were dried and evaporated. Crystallization with fumaric acid fromisopropanol/ether gave the title compound in 220 mg yield. (Compound11). M.p. 108°-109° C.

The following compounds were made in exactly the same manner using theappropriate alcohol instead of 1-hexanol:

3-(3-(5-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate, M.p. 107°-110° C. (Compound 48).

3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate, M.p. 135.5°-137.5° C. (Compound 49).

3-(3-Pentyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane oxalate,M.p. 102°-104° C. (Compound 50).

3-(3-Isopentyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate, M.p. 135.5°-137.5° C. (Compound 51).

EXAMPLE 9 3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane fumarate

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (500 mg, 1.56 mmol), sodiumhydrogen sulfide,monohydrate (463 mg, 6.25 mmol) and potassium carbonate (1.38 g, 10mmol) in DMF (20 ml) was stirred at room temperature for 1 h.1-Pentylbromide (755 mg, 5 mmol) was added, and the reaction mixture wasstirred at room temperature for 18 h. 1N HCl was added, and the mixtureextracted with ether once. 50% NaOH was added to the aqueous phase andextracted with ether. The ether phase was dried and evaporated.Crystallization of the residue with fumaric acid from isopropanol/ethergave the title compound in 380 mg yield. (Compound 12). M.p. 138°-139°C.

EXAMPLE 10

The following compounds were made in exactly the same manner asdescribed in example 9, using the appropriate alkyl halogenide:

3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate. (Compound 13). M.p. 85°-87° C.

3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate. (Compound 14). M.p. 138°-139° C.

3-(3-(3-Phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane fumarate. (Compound 44). M.p. 123°-124° C.

3-(3-(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate. (Compound 45). M.p. 200° C. decomp.

3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane oxalate,M.p. 194°-195° C. (Compound 52).

3-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate, M.p. 206.5°-208° C. (Compound 53).

3-(3-Heptylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate, M.p. 130°-132° C. (Compound 54).

EXAMPLE 11

A. Ethyl(1-azabicyclo 3.2.1!octan-6-ylidene)cyano acetate

A solution of 1-azabicyclo 3.2.1!octan-6-one (41.25 g, 0.33 mol), aceticacid (2 ml), ammonium acetate (1.25 g) and ethyl cyanoacetate (37 g,0.33 mol) in toluene (500 ml) was refluxed with a Dean-Stark waterseparator for 40 h. The toluene phase was extracted with 3×200 ml 5M HClsolution. The water phase was basified with 28% ammonium hydroxidesolution and extracted with ether (4×200 ml). The organic phases weredried over magnesium sulfate and evaporated. The residue was purified bycolumn chromatography (eluent CH₂ Cl₂ /MeOH (9:1), yield 41 g of thetitle compound.

B. Ethyl(1-azabicyclo 3.2.1!octan-6-yl)cyanoacetate

A solution of ethyl(1-azabicyclo 3.2.1!octan-6-ylidene)cyanoacetate (41g, 0.19 mol) in abs. ethanol (500 ml) was treated with 10% palladium oncarbon (5 g) and hydrogen in a Parr shaker at 30 psi for 5 h. Filtrationand evaporation gave the title compound in 36 g yield.

C. (1-azabicyclo 3.2.1!octan-6-yl)hydroxyiminoacetonitrile

Ethyl(1-azabicyclo 3.2.1!octan-6-yl)cyanoacetate (36 g, 0.16 mol) inabs. ethanol (100 ml) was added to a solution of sodium (4 g, 0.21 mol)in abs. ethanol (100 ml). Isoamylnitrite (25 ml, 0.19 mol) was addedover 0.5 h, and the mixture was heated at 50° C. for 4 h. Evaporation ofthe reaction mixture gave crude sodium salt of the title compound, whichwas used without further purification.

D. 6-Chloro-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane

A solution of crude (1-azabicyclo3.2.1!octan-6-yl)hydroxyiminoacetonitrile (max. 0.16 mol) in DMF (150ml) was added to a solution of S₂ Cl₂ (50 ml, 0.68 mol) in DMF (100 ml)at 0° C. over 1 h. The reaction mixture was stirred over night and icewater (500 ml) was added. The mixture was filtered and the filter cakewashed with 1M HCl (3×100 ml). The water solution was extracted withether (2×200 ml), then basified with a 28% ammonium hydroxide solutionand extracted with ether (4×200 ml). The combined ether extracts fromthe last extraction were dried and evaporated. The residue was purifiedby column chromatography (eluent: CH₂ Cl₂ /MeOH (9:1)) to give the titlecompound in 11 g yield as a mixture of the endo and exo forms.

EXAMPLE 12

The following compound was made in exactly the same manner as describedin example 11, starting from 1-azabicyclo 2.2.1!heptan-3-one:

3-Chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptane.

EXAMPLE 13 Exo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane and Endo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane-oxalate

A solution ofEndo/Exo-6-chloro-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (1.3 g, 5 mmol) in abs. ethanol (100 ml) was treated with10% palladium on carbon (300 mg) in a Parr shaker at 20 psi for 4 h. Thesolution was filtered and evaporated. The residue was purified by columnchromatography with CH₂ Cl₂ /MeOH/TEA (9:1:0.25). The first fractioncontained the exo compound, which after crystallization with oxalic acidin acetone, was collected in 150 mg yield. (Compound 15). M.p. 148°-149°C. The next fractions contained the endo compound, which aftercrystallization with oxalic acid from acetone was collected in 600 mgyield. (Compound 16). M.p. 195°-197° C.

EXAMPLE 14 Endo-6-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

To a solution of endo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (229 mg, 1.0 mmol) in DMF (10 ml) was addedsodiumhydrogensulfide monohydrate (230 mg, 3.1 mmol). The reactionmixture was stirred at room temperature for 1 h. Potassium carbonate(1.38 g, 10 mmol) and 1-hexylbromide (335 mg, 2.5 mmol) was added andthe mixture was stirred for 1 h. 1N HCl solution was added and themixture extracted with ether (2×50 ml). The aqueous solution wasbasified with a 28% NH₃ solution and extracted with methylene chloride(3×100 ml). The methylene chloride phase was dried and evaporated. Theresidue was purified by column chromatography (eluent CH₂ Cl₂ /MeOH(9:1)). Crystallization of the pure base with oxalic acid from acetonegave the title compound in 100 mg yield. (Compound 17). M.p. 137°-139°C.

EXAMPLE 15

The following compounds were made in exactly the same manner asdescribed in Example 14, using the appropriate alkyl bromide:

Endo-6-(3-(5-hexenylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate. (Compound 18). M.p. 113°-114° C.

Endo-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 24). M.p. 123°-124° C.

Endo-6-(3-ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 25). M.p. 150°-151° C.

Endo-6-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 26). M.p. 137°-138° C.

Endo-6-(3-(3-phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate. (Compound 27). M.p. 127°-129° C.

Endo-6-(3-(4-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 28). M.p. 159°-161° C.

Endo-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate (Compound 57) M.p. 132°-134° C.

EXAMPLE 16 Exo-6-(3-ethoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate andEndo-6-(3-ethoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate

To a solution of sodium (230 mg, 10 mmol) in abs. ethanol (20 ml) wasadded endo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane(229 mg, 1 mmol). The reaction mixture was heated at 50° C. for 12 h andevaporated. Water (100 ml) was added, and the mixture was extracted withmethylene chloride (4×50 ml). The organic phases were dried andevaporated. The residue was purified by column chromatography eluent(CH₂ Cl₂ MeOH/TEA, 9:1:0.25). The first fractions contained the exocompound, which after crystallization with oxalic acid in acetone wascollected in 50 mg yield. (Compound 19). M.p. 110°-112° C. The nextfractions contained the endo compound, which after crystallization withoxalic acid in acetone was collected in 20 mg yield. (Compound 20). M.p.127°-129° C.

EXAMPLE 17 Exo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate andEndo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptaneoxalate

A solution ofendo/exo-3-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane (0.5 g, 2 mmol) in abs. ethanol (100 ml) was treated with10% palladium on carbon in a Parr shaker at 20 psi for 4 h. The solutionwas filtered and evaporated. The residue was purified by columnchromatography, eluent CH₂ Cl₂ /MeOH (9:1). The first fractionscontained the exo compound, which after crystallization with oxalic acidfrom acetone/ether was collected in 50 mg yield. (Compound 21). M.p.138°-140° C. The next fractions contained the endo compound, which aftercrystallization with oxalic acid from acetone, was collected in 450 mgyield. (Compound 22). M.p. 118°-121° C.

EXAMPLE 18 Endo-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate

To a solution of sodium (110 mg, 5 mmol) in methanol (20 ml) was addedendo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptane (110mg, 0.5 mmol). The reaction mixture was heated at reflux for 60 h andevaporated. Water (50 ml) was added, and the mixture was extracted withmethylene chloride (4×50 ml). The organic phases were dried andevaporated. The residue was purified by column chromatography eluent(CH₂ Cl₂ /MeOH, 9:1). Crystallization of the free base with oxalic acidfrom acetone/ether gave the title compound in 40 mg yield. (Compound23). M.p. 104°-106° C.

EXAMPLE 19 Exo-6-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

To a solution of exo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (229 mg, 1.0 mmol) in DMF (20 ml) was addedsodiumhydrogensulfide monohydrate (230 mg, 3.0 mmol). The reactionmixture was stirred at room temperature for 1 h. Potassium carbonate(1.38 g, 10 mmol) and 1-hexylbromide (335 mg, 2.5 mmol) was added andthe mixture was stirred for 1 h. 1N HCl solution was added and themixture extracted with ether (2×50 ml). The aqueous solution wasbasified with a 28% NH₃ solution and extracted with ether (2×50 ml). Theether phase was dried and evaporated. The residue was crystallized asthe oxalate salt from acetone/ether in 200 mg yield. (Compound 29). M.p.118°-119° C.

EXAMPLE 20

The following compounds were made in exactly the same manner asdescribed in example 19, using the appropriate alkylbromide:

Exo-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 30). M.p. 143°-145° C.

Exo-6-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 31). M.p. 117°-118° C.

Exo-6-(3-ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 32). M.p. 159°-160° C.

Exo-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate (Compound 58), M.p. 173°-174° C.

EXAMPLE 21 Endo-3-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane fumarate

To a solution of endo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane (215 mg, 1.0 mmol) in DMF (20 ml) was added sodiumhydrogensulfide monohydrate (230 mg, 3.0 mmol). The reaction mixture wasstirred at room temperature for 1 h. Potassium carbonate (1.38 g, 10mmol) and 1-pentylbromide (0.45 g, 3 mmol) was added and the mixture wasstirred for 1 h. 1M hydrochloric acid solution (100 ml) was added andthe mixture extracted with ether (2×50 ml). The aqueous solution wasbasified with a 28% NH₃ -solution and extracted with ether (3×75 ml).The ether phase was dried and evaporated. The residue was crystallizedas the fumarate salt from MeOH/ether in 250 mg yield. (Compound 33).M.p. 120°-122° C.

EXAMPLE 22

The following compounds were made in exactly the same manner asdescribed in example 21 using the appropriate alkylbromide:

Endo-3-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptanefumarate. (Compound 34). M.p. 127°-129° C.

Endo-3-(3-(3-phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate. (Compound 35). M.p. 119°-120° C.

Endo-3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptanefumarate. (Compound 36). M.p. 106°-108° C.

Endo-3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptaneoxalate. (Compound 37). M.p. 169°-170° C.

EXAMPLE 23 Exo-3-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate

To a solution of exo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane (215 mg, 1.0 mmol) in DMF (20 ml) was added sodiumhydrogensulfide monohydrate (230 mg, 3.0 mmol). The reaction mixture wasstirred at room temperature for 1 h. Potassium carbonate (1.38 g, 10mmol) and 1-pentylbromide (0.45 g, 3 mmol) was added and the mixture wasstirred for 1 h. 1M hydrochloric acid solution (100 ml) was added andthe mixture extracted with ether (2×50 ml). The aqueous solution wasbasified with a 28% NH₃ -solution and extracted with ether (3×75 ml).The ether phase was dried and evaporated. The residue was crystallizedas the oxalate salt from MeOH/ether in 250 mg yield. (Compound 38). M.p.120°-122° C.

EXAMPLE 24

The following compounds were made in exactly the same manner asdescribed in example 23, using the appropriate alkylbromide:

Exo-3-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptaneoxalate. (Compound 39). M.p. 102°-103° C.

Exo-3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptaneoxalate. (Compound 40). M.p. 132°-133° C.

Exo-3-(3-(3-phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate. (Compound 41). M.p. 126°-127° C.

Exo-3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptaneoxalate. (Compound 42). M.p. 188°-189° C.

EXAMPLE 25

A. 8-Ethoxycarbonyl-3-chloro-2-formyl-8-azabicyclo 3.2.1!oct-2-ene

To a solution of dry DMF (45 g, 0.6 mol) in dry CH₂ Cl₂ (150 ml) wasadded POCl₃ (75 g, 0.5 mol) at 0°-10° C. 8-Ethoxycarbonyl-8-azabicyclo3.2.1!octane-3-one (57 g, 0.29 mol) dissolved in dry CH₂ Cl₂ (60 ml) wasadded. The reaction mixture was stirred over night at room temperature,then added to ice water (1.000 ml). The phases were separated and thewater phase extracted with CH₂ Cl₂ (2×200 ml). The combined CH₂ Cl₂extracts were washed with a saturated NaHCO₃ solution and water, driedand evaporated to give 70 g of the title compound, which was used in thenext step without further purification.

B.8-Ethoxycarbonyl-3-chloro-2-(3-chloro-1,2,5-thiadiazol-4-yl)-8-azabicyclo3,2,1!oct-2-ene

Potassium cyanide (8.5 g, 0.13 mol) and ammonium chloride (6.4 g, 0.12mol) were dissolved in a min. amount of water.8-Ethoxycarbonyl-3-chloro-2-formyl-8-azabicyclo 3.2.1!oct-2-ene (23 g,0.1 mol) dissolved in DMF (25 ml) was added. The reaction mixture wasstirred at room temperature for 3 days, then added to a 5N hydrochloricacid solution (200 ml). The aqueous phase was extracted with ether (3×75ml), then basified with a 28% NH₃ solution and extracted with ether(4×100 ml). The ether phases from the last extraction were dried,evaporated and dissolved in DMF (50 ml). This solution was added tosulphur monochloride (16.8 g, 0.12 mol) in DMF (50 ml). The reactionmixture was stirred over night at room temperature and poured intoice-water. The water phase was extracted with ether (3×100 ml). Thecombined ether phases were dried and evaporated. The residue waspurified by column chromatography (eluent: CH₂ Cl₂). Yield 3.2 g as anoil.

EXAMPLE 26 3-Chloro-2-(3-ethoxy-1,2,5-thiadiazol-4-yl)-8-azabicyclo3.2.1!oct-2-ene oxalate

To a solution of sodium (230 mg, 10 mmol) in abs. ethanol (50 ml) wasadded8-ethoxycarbonyl-3-chloro-2-(3-chloro-1,2,5-thiadiazol-4-yl)-8-azabicyclo3.2.1!oct-2-ene(670 mg, 2 mmol). The reaction mixture was heated at reflux overnight,evaporated and conc. HCl (40 ml) was added. The reaction mixture washeated at reflux for 4 days, evaporated and basified with a 28% NH₃solution. The aqueous solution was extracted with ether (3×75 ml). Thecombined ether extracts were dried and evaporated. The residue waspurified by column chromatography (eluent CH₂ Cl₂ /MeOH-9:1).Crystallization of the free base with oxalic acid in acetone gave thetitle compound in 110 mg yield. (Compound 43). M.p. 178°-180° C.

EXAMPLE 27 3-Chloro-2-(3-chloro-1,2,5-thiadiazol-4-yl)-8-azabicyclo3.2.1!oct-2-ene oxalate

To a solution of8-Ethoxycarbonyl-3-chloro-2-(3-chloro-1,2,5-thiadiazol-4-yl)-8-azabicyclo3.2.1!oct-2-ene(1.7 g, 5 mmol) in dry toluene (50 ml) was added AlCl₃ (2.6 g, 20 mmol).The reaction mixture was slowly heated to 80° C. and kept at thistemperature for 10 min. After cooling to room temperature the reactionmixture was poured on ice and basified with a 50% NaOH solution. Theaqueous phase was extracted with CH₂ Cl₂ (3×100 ml). The combinedorganic extracts were dried over MgSO₄ and evaporated. The residue wascrystallized as the oxalate salt from acetone to give the titlecompound. Yield 1.6 g (Compound 47), M.p. 194°-195° C.

EXAMPLE 28

The following compounds were made in exactly the same manner asdescribed in Example 16 using the appropriate alcohol:

Exo-6-(3-pentyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate (Compound 59), M.p. 122°-123° C.

Endo-6-(3-pentyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate (Compound 60), M.p. 124°-125° C.

EXAMPLE 29

A. 4-Chloro-3-formyl-1-azabicyclo 3.3.1!non-2-ene

To DMF (50 ml, 0.68 mol) was slowly added POCl₃ (50 ml, 0.54 mol) at 0°C. over 1 h. 1-Azabicyclo 3.3.1!nonane-4-one hydrochloride (17.5 g, 0.1mol) was added in one portion and the reaction mixture heated at 100° C.for 1 h. After cooling the reaction mixture was poured on ice (1000 g)and the reaction mixture neutralized with potassium carbonate. The waterphase was extracted with ether (5×200 ml). The organic phase was driedover MgSO₄ and evaporated. The residue was purified by columnchromatography (eluent: CH₂ Cl₂ /CH₃ OH (9:1)), yielding 17 g of thetitle compound.

B. 4-Chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene oxalate

To a solution of oxalic acid (9.0 g, 100 mmol) in water (100 ml) wasadded 4-chloro-3-formyl-1-azabicyclo 3.3.1!non-2-ene (17.0 g, 95 mmol).Potassium cyanide (6.8 g, 10 mmol) dissolved in a min. amount of waterwas added dropwise. The reaction mixture was stirred at room temperaturefor 2 h. The precipitated crystals were filtered and suspended inwater/EtOH (4:1, 120 ml). Ammonium chloride (6.0 g, 100 mmol) andammonium hydroxide (28% in water 10 ml) was added and the reactionmixture was stirred at room temperature overnight. The water phase wasextracted with methylene chloride (5×100 ml). The organic phases weredried over magnesium sulphate and evaporated. The residue was dissolvedin DMF (50 ml) and added dropwise to a solution of sulfurmonochloride(20 ml, 250 mmol) in DMF (30 ml) at 0° C. The reaction mixture wasstirred at room temperature for 4 h, then crushed ice (500 g) was added.The precipitated sulfur was filtered off and the filtrate washed with 1Mhydrochloric acid solution (2×100 ml) the combined water phases wasbasified with ammonia (28% in water) and extracted with ether (4×200ml). The combined organic phases were dried and evaporated. The residuewas crystallized as the oxalate salt from acetone/ether to give thetitle compound. Yield 10.8 g (Compound 61), M.p. 149°-150° C.

EXAMPLE 30 4-Chloro-3-(3-propyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene oxalate

To a solution of sodium (0.23 g, 10 mmol) in n-propanol (10 ml) wasadded 4-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene (0.274 g, 1 mmol). The reaction mixture was heated at60° C. for 2 h. Hydrochloric acid (1M, 100 ml) was added, and the waterphase extracted with ether (2×50 ml). The water phase was basified withsolid potassium carbonate and extracted with ether (3×75 ml). Thecombined ether extracts were dried over magnesium sulfate andevaporated. The residue was crystallized as the oxalate salt fromacetone/ether to give the title compound. Yield 180 mg (Compound 62),M.p. 122°-123° C.

EXAMPLE 31

The following compounds were made in exactly the same manner asdescribed in example 30 using the appropriate alcohol:

4-Chloro-3-(3-pentyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene oxalate (Compound 63), M.p. 114°-115° C.

4-Chloro-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene oxalate (Compound 64), M.p. 103°-104° C.

EXAMPLE 32 4-Chloro-3-(1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene oxalate

To a solution of sodium (0.092 g, 4 mmol) in isopropanol (40 ml) wasadded n-butylmercaptan (270 ml, 3 mmol).4-Chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.3.1!non-3-ene(0.82 g, 3 mmol) dissolved in isopropanol (10 ml) was added and thereaction mixture was stirred overnight at room temperature. The reactionmixture was evaporated and hydrochloric acid (1M, 100 ml) was added. Thewater phase was extracted with ether (2×50 ml) basified with solidpotassium carbonate and extracted with ether (3×75 ml). The organicphase was dried and evaporated. The residue was purified by columnchromatography (eluent: ethyl acetate) and the free base wascrystallized with oxalic acid from acetone to give the title compound.Yield 250 mg (Compound 65) M.p. 175°-77° C.

EXAMPLE 33 (-)3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (+)L-tartrate

To a solution of 3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (free base of compound 13, example 10) (5.5 g, 19.43 mmol)in ethanol (50 ml) was added a solution of (+)L-tartaric acid (2.9 g,19.4 mmol) in water (10 ml). Ether (approx. 200 ml) was added to thesolution to give a slightly unclear solution. The title compound wasprecipitated overnight and the crystals collected by filtration (3.05g). Recrystallization twice from ethanol (20 ml) and ether gave the pure(-)enantiomer (1.90 g) (Compound 55), M.p. 106°-108° C. α!(freebase)=-15.80° (C=4.05 MeOH).

EXAMPLE 34 (+)3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (-)D-tartrate

The mother liquour from the crystallization with (+)L-tartaric acid(example 33) was evaporated and the residue treated with 50% NaOH inwater and extracted with ether. The combined ether phase were dried andevaporated to give crude free base of the title compound (2.9 g, 10.2mmol). The residue was dissolved in ethanol (15 ml) and a solution of(-)D-tartaric acid (1.54 g, 10.2 mmol) in water (4 ml) was added. Etherwas added to the solution and the title compound precipitated overnight.The crystals were collected by filtration and recrystallization twicefrom ethanol/ether gave the pure (+)enantiomer (1.90 g) (Compound 56),M.p. 106°-108° C. α!(free base)=+14.94° (C=4.09 in MeOH).

EXAMPLE 35 3-(3-Amino-1,2,5-oxadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate

To a solution of crude (1-azabicyclo2.2.2!octan-3-yl)hydroxyiminoacetonitrile (10 g, max. 29 mmol) (example1C) in methanol (50 ml) was added a methanol solution of hydroxylamine(prepared from NH₂ OH, HCl (4.2 g, 60 mmol) in methanol (60 ml) andsodium (1.38 g, 60 mmol) in methanol (60 ml). The reaction mixture wasstirred at 40° C. for 18 h and evaporated to give the crude amide oximederivative. The residue was treated with excess of POCl₃ at 45° C. for18 h. Water and sodium hydroxide was added to obtain alkaline pH and theaqueous mixture extracted with chloroform. The combined organic phaseswere dried and evaporated to give the free base of the title compound asa solid (yield 570 mg). MS: M⁺ : 194. Crystallization as the fumaratesalt from isopropanol gave the title compound (110 mg) (Compound 66),M.p. 60°-75° C.

EXAMPLE 36

A. 5-Carboxaldehyde-1-azabicyclo 3.2.1!octane

To a solution of 1-azabicyclo3.2.1!oct-5-yl-N-methyl-N-methoxycarboxamide (4.0 g, 17.4 mmol) intetrahydrofuran (100 ml) was added dropwise a 1 Molar solution of DIBAL(26 ml, 26 mmol) at -65° C. The temperature of the reaction mixture wasallowed to raise to 0° C. over 30 min. and then cooled to -65° C.Aqueous hydrochloric acid (75 ml, 5N) was added to the cold reactionmixture and the tetrahydrofuran was evaporated in vacuo. The aqueousresidue was stirred overnight at room temperature and then evaporated.Water and potassium carbonate was added to the residue and extractedwith methylene chloride (3×300 ml). The combined methylene chloridephases were dried and evaporated to give the title compound as an oil.Yield 2.75 g.

B. 2-Amino-2-(1-azabicyclo 3.2.1!oct-5-yl)acetonitrile

To a solution of potassium cyanide (1.43 g, 22 mmol) in water (20 ml)5-carboxaldehyde-1-azabicyclo 3.2.1!octane (2.75 g, 19.8 mmol) was addedover 30 min. at 0°-10° C. Acetic acid (1.26 ml, 22 mmol) was added tothe reaction mixture over 30 min. at 5°-10° C. The reaction mixture wasstirred at room temperature for further 18 h and cooled to 5° C. Aqueoussodium hydroxide was added to obtain alkaline pH and then extracted withmethylene chloride (3×200 ml). The combined organic phases wereevaporated and the residue was treated with a solution of ammoniumchloride (3.8 g, 72 mmol) in water (10 ml) and 25% aqueous ammonia (5ml). The reaction mixture was stirred at room temperature for 18 h andthen extracted with methylene chloride. The combined organic phases weredried and evaporated to give the title compound. Yield. 1.67 g.

C. 5-(3-Chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane oxalate

2-Amino-2-(1-azabicyclo 3.2.1!oct-5-yl)acetonitrile (1.67 g, 10 mmol)was dissolved in DMF (10 ml) and a solution of sulfur monochloride (2.57ml, 30 mmol) in DMF (10 ml) was added dropwise at 0° C. The reactionmixture was stirred at room temperature for 18 h and cooled to 0° C.whereupon water (40 ml) and aqueous potassium hydroxide was addedslowly. The alkaline reaction mixture was extracted with ether (3×300ml) and the combined ether phases were dried and evaporated. The residue(850 mg) was crystallized with oxalic acid from acetone/methanol to givethe title compound. Yield 710 mg (Compound 67), M.p. 137.5°-139.5° C.

EXAMPLE 37 5-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

Sodium hydrosulfide monohydrate (326 mg, 4.4 mmol) was added to asolution of 5-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate (350 mg, 1.1 mmol) in DMF (20 ml) at room temperature and thereaction mixture was stirred for 30 min. Potassium carbonate (1.24 g, 9mmol) and 1-bromohexane (561 μl, 4 mmol) were added and the reactionmixture was stirred for 3 h. Water (50 ml) was added to the reactionmixture and the aqueous phase extracted with ether (3×200 ml). Thecombined ether phases were dried and evaporated to give the crude freebase of the title compound (220 mg). The residue was crystallized as theoxalate salt from acetone to give the title compound. Yield 200 mg(Compound 68), M.p. 67°-69° C.

EXAMPLE 38 Exo-3-(3-methylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate

To a solution of exo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane (215 mg, 1.0 mmol) in DMF (20 ml) was addedsodiumhydrogensuifide monohydrate (230 mg, 3.0 mmol). The reactionmixture was stirred at room temperature for 1 h. Potassium carbonate(1.38 g, 10 mmol) and methyliodide (0.42 g, 3 mmol) were added and themixture stirred at room temperature for 0.5 h. 1N hydrochloric acidsolution (100 ml) was added and extracted with ether (2×50 ml). Theaqueous solution was basified with a 28% NH₃ solution and extracted withether (3×75 ml). The combined ether phases were dried and evaporated.The residue was crystallized as the oxalate salt from acetone in 180 mgyield. (Compound 69). M.p. 133°-139° C.

EXAMPLE 39

The following compound was made in exactly the same manner as describedin example 38, using ethyliodide:

Exo-3-(3-ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptaneoxalate from ethyliodide andexo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptane.(Compound 70). M.p. 156°-157° C.

Exo-3-(3-(4-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate fromexo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!-heptane and4-cyanobenzylchloride. (Compound 173). M.p. 200°-201° C.

EXAMPLE 40

The following compounds were made in exactly the same manner asdescribed in example 38 using endo3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptane and theappropriate alkylhalogenide.

Endo-3-(3-(2-phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate from 2-phenoxyethylbromide and endo3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptane. (Compound71). M.p. 127°-130° C.

Endo-3-(3-(2-thienyl)propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate from 1-chloro-3-(2-thienyl)propane andendo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptane.(Compound 72). M.p. 123°-126° C.

Endo-3-(3-(2-phenylthio)ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.1!heptane oxalate from 1-chloro-2-(phenylthio)ethane andendo-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.1!heptane.(Compound 73). M.p. 143°-145° C.

EXAMPLE 41 Exo-6-(3-methylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

To a solution of exo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (229 mg, 1.0 mmol) in DMF (20 ml) was addedsodiumhydrogensulfide monohydrate (230 mg, 3.0 mmol). The reactionmixture was stirred at room temperature for 1 h. Potassium carbonate(1.38 g, 10 mmol) and methyliodide (0.42 g, 3 mmol) were added and themixture stirred for 1 h. 1N hydrochloric acid solution (100 ml) wasadded and the mixture extracted with ether (2×50 ml). The aqueoussolution was basified with a 28% NH₃ solution and extracted with ether(3×75 ml). The combined ether phases were dried and evaporated. Theresidue was crystallized as the oxalate salt from acetone in 200 mgyield. (Compound 74). M.p. 141°-142° C.

EXAMPLE 42

The following compounds were made in exactly the same manner asdescribed in example 41 using the appropriate alkylhalogenide:

Exo-6-(3-heptylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate from exo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane and 1-bromoheptane. (Compound 75). M.p. 111°-112° C.

Exo-6-(3-isohexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate from exo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane and 1-bromo-4-methylpentane. (Compound 76). M.p. 128°-130°C.

Exo-6-(3-isopentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octanefrom exo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneand 1-bromo-3-methylbutane. (Compound 77). M.p. 130°-132° C.

Exo-6-(3-(4-cyanobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-4-cyanobutane. (Compound 78). M.p. 148°-150° C.

Exo-6-(3-cyanomethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane andchloroacetonitrile. (Compound 79). M.p. 141°-142° C.

Exo-6-(3-(2-cyanoethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-2-cyanoethane. (Compound 80). M.p. 151°-152° C.

Exo-6-(3-(3-cyanopropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-3-cyanopropane. (Compound 81). M.p. 114°-115° C.

Exo-6-(3-(4-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and4-cyanobenzylchloride. (Compound 82). M.p. 198°-199° C.

Exo-6-(3-(3-phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-3-phenylpropane. (Compound 83). M.p. 149°-150° C.

Exo-6-(3-(2-phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-2-phenoxyethane. (Compound 133). M.p. 137°-144° C.

Exo-6-(3-benzylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate from exo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane and benzylchloride. (Compound 134). M.p. 153°-155° C.

Exo-6-(3-(2-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 223) M.p. 107°-110° C. fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and2-cyanobenzylbromide.

Exo-6-(3-(3-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 224) M.p. 154°-156° C. fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and3-cyanobenzylbromide.

Exo-6-(3-(2-trifluoromethylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octaneoxalate (Compound 225) M.p. 135°-138° C. fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and2-trifluoromethylbenzylbromide.

Exo-6-(3-(3-trifluoromethylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octaneoxalate (Compound 226) M.p. 152°-155° C. fromexo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and3-trifluoromethylbenzylbromide.

EXAMPLE 43

The following compounds were made in exactly the same manner asdescribed in example 41 by reactingendo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane withthe appropriate alkylhalogenide:

Endo-6-(3-(2-phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromendo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-2-phenoxyethane. (Compound 84). M.p. 150°-155° C.

Endo-6-(3-methylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate from endo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane and methyliodide. (Compound 85). M.p. 150°-151° C.

Endo-6-(3-isopentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate from endo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane and 1-bromo-3-methylbutane. (Compound 86). M.p. 118°-120°C.

Endo-6-(3-isohexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate from endo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane and 1-bromo-4-methylpentane. (Compound 87). M.p. 110°-112°C.

Endo-6-(3-benzylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate from endo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane and benzylchloride. (Compound 88). M.p. 110°-112° C.

Endo-6-(3-cyanomethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromendo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane andchloroacetonitrile. (Compound 89). M.p. 158°-59° C.

Endo-6-(3-(2-cyanoethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromendo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-2-cyanoethane. (Compound 90). M.p. 160°-161° C.

Endo-6-(3-(3-cyanopropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromendo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-3-cyanopropane. (Compound 91). M.p. 119°-120° C.

Endo-6-(3-(4-cyanobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromendo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and1-bromo-4-cyanobutane. (Compound 92). M.p. 150°-151° C.

Endo-6-(3-(2-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 227) M.p. 210°-211° C. fromendo-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and2-cyanobenzylbromide.

EXAMPLE 44 4-Chloro-3-(3-butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene oxalate

To a solution of sodium (0.23 g, 10 mmol) in n-butanol (10 ml) was added4-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.3.1!non-3-ene(Compound 61) (0.274 g, 1 mmol). The reaction mixture was heated at 60°C. for 4 h. Water (100 ml) was added and the water phase extracted withether (3×50 ml). The combined ether extracts were dried over magnesiumsulfate and evaporated. The residue was crystallized from acetone/etherto give the title compound in 200 mg yield. (Compound 93). M.p.104°-107° C.

EXAMPLE 45 4-Chloro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene hydrochloride

The compound was made as described in example 44 by reacting4-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.3.1!non-3-enewith 1-hexanol. The free base was crystallized as the hydrochloride fromether. (Compound 94). M.p. 100°-101° C.

EXAMPLE 46 3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene oxalate

To a solution of4-chloro-3-(3-butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.3.1!non-3-ene(0.63 g, 2.0 mmol) in abs. ethanol (20 ml), triethyl amine (3 ml) andformic acid (1 ml) were added. The reaction mixture was heated to 80° C.under nitrogen. At this temperature palladium on carbon (0.5 g, 5%) wasadded in one portion. After 15 min. another portion of palladium oncarbon (0.25 g, 5%) was added. The last addition of palladium on carbonwas repeated twice. After cooling, the reaction mixture was filtered andevaporated. The residue was dissolved in water basified with potassiumcarbonate and extracted with ether (3×75 ml). The ether extracts weredried and evaporated. The crude compound was purified by columnchromatography (eluent: CH₂ Cl₂ /MeOH (9:1)), yielding 80 mg of freebase. The title compound was crystallized with oxalic acid fromacetone/ether in 80 mg yield. (Compound 95). M.p. 150°-151° C.

EXAMPLE 47

The following compounds were prepared in exactly the same manner asdescribed in example 46.

3-(3-Methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.3.1!non-3-ene oxalatefrom 4-chloro-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene. (Compound 96). M.p. 200°-201° C.

3-(3-Propoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.3.1!non-3-ene oxalatefrom 4-chloro-3-(3-propoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene. (Compound 97). M.p. 166°-167° C.

3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.3.1!non-3-eneoxalate from 4-chloro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene. (Compound 98). M.p. 100°-101° C.

EXAMPLE 48 3-(3-Isopentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane fumarate

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (Compound 8) (420 mg, 1.83 mmol), sodiumhydrogen sulfidemonohydrate (245 mg, 3.70 mmol) and potassium carbonate (780 mg, 5.64mmol) in DMF (20 ml) was stirred at room temperature for 2 h. A solutionof 1-bromo-3-methylbutane (420 mg, 2.75 mmol) in DMF (5 ml) was added,and the reaction mixture was stirred at room temperature for 3 h. Water(20 ml) was added and the mixture was extracted with ethyl acetate(3×100 ml). The combined extract was washed with brine, dried (MgSO₄),filtered and evaporated. The residue was purified by columnchromatography (eluent: CH₂ Cl₂ :MeOH:NH₄ OH (8:2:0.5%)) to give thefree base of the desired product in 400 mg yield. Crystallization of theresidue with fumaric acid from isopropanol/ether gave the title compoundin 370 mg yield. (Compound 99). M.p. 130°-132° C.

The following compounds were made as described above using the indicatedalkylhalogenide instead of 1-bromo-3-methylbutane:

3-(3-(1-Methylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane fumarate (Compound 100), using 2-bromobutane.

3-(3-Isobutylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octanefumarate (Compound 101), using 1-bromo-2-methylpropane.

3-(3-(2-Phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane fumarate (Compound 102), using β-bromophenetole. M.p.135°-137° C.

3-(3-Cyanomethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate (Compound 103), using chloroacetonitrile. M.p. 188°-189° C.

3-(3-(3-(2-Thienyl)propylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane fumarate (Compound 104), using1-chloro-3-(2-thienyl)propane. M.p. 134°-136° C.

3-(3-(4-Chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (Compound 105), using 1-bromo-4-chlorobutane.

3-(3-Methylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane oxalate(Compound 131) using bromomethane. M.p. 185°-187° C.

3-(3-(N-(2-Ethylthio)phthalimide)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 135) using N-(2-bromoethyl)phthalimide.M.p. 160°-161° C.

3-(3-(2-Methoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 136) using 2-methoxyethylbromide. M.p.124°-125° C.

3-(3-(2-(1,3-Dioxolan-2-yl)ethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 137) using2-(1,3-dioxolan-2-yl)ethylbromide. M.p. 151°-153° C.

3-(3-(4-Pyridylmethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 138) using 4-(chloromethyl)pyridine. M.p.155°-157° C.

3-(3-Cyclopropylmethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 139) using cyclopropylmethylbromide. M.p.217°-218° C.

3-(4-Fluorobenzylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate (Compound 140) using 4-fluorobenzylbromide.

3-(3-(2-Hydroxybutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 214) M.p. 180°-182° C., from1-bromo-2-hydroxybutane.

3-(3-(2-Butanonylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate (Compound 215) M.p. 197°-198° C., from 1-bromo-2-butanone.

3-(3-(3-Phenoxybenzyloxy)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 216) M.p. 117°-120° C., from1-hydroxymethyl-3-phenoxybenzene.

3-(3-(4-Carboxybutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane hydrochloride (Compound 217) M.p. 122°-124° C., from1-bromo-4-carboxybutane.

3-(3-(3-Hydroxybutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 218) M.p. 140°-141° C., from1-bromo-3-hydroxybutane.

3-(3-(4-Hydroxybutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 219) M.p. 160°-161° C., from1-bromo-4-hydroxybutane.

EXAMPLE 493-(3-(1-Methyltetrazol-5-ylthio)butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate

A solution of3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane (Compound 105) (3.0 g, 9.5 mmol), potassium carbonate (10g, 72 mmol) and 1-methyl-5-mercaptotetrazole (5.0 g, 43 mmol) in DMF (50ml) was stirred at room temperature for 3 days. 1N hydrochloric acid wasadded to the reaction and the mixture was extracted with ether. Theether phase was discharged. The reaction mixture was made basic with 4Nsodium hydroxide and then extracted with ether (3×150 ml). The combinedether phases were dried (MgSO₄) and evaporated. The residue wascrystallized with oxalic acid from acetone to give the title compound in420 mg yield. (Compound 106). M.p. 78°-80° C.

The following compounds were made as described above using the indicatedmercapto derivative instead of 1-methyl-5-mercaptotetrazole:

3-(3-(2-Methyl-1,3,4-thiadiazol-5-ylthio)butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 107), using2-mercapto-5-methyl-1,3,4-thiadiazole. M.p. 104°-105° C.

3-(3-(4-(2-Benzothiazolyl)thio)butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 108), using 2-mercaptobenzothiazole. M.p.51°-53° C.

EXAMPLE 50 3-(3-(4-Ethylbenzyloxy)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate

To a solution of 4-ethylbenzyl alcohol (1.63 g, 12 mmol) in dry THF (20ml) was added sodium hydride (50% dispersion in mineral oil) (50 mg, 12mmol) at 0° C. The reaction mixture was stirred for 1 h, then a solutionof 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane (920 mg,4 mmol) in THF was added dropwise. The reaction mixture was stirred for3 h. 1N hydrochloric acid was added to the reaction mixture andextracted with ether. The ether phase was discharged. The reactionmixture was made basic with 4N sodium hydroxide and extracted with ether(3×200 ml). The combined ether phases were dried and evaporated. Theresidue was purified by column chromatography (eluent: CH₂ Cl₂ :MeOH:NH₄OH (8:2:0.5%)). Crystallization with oxalic acid from acetone gave thetitle compound in 180 mg yield. (Compound 109). M.p. 100°-102° C.

EXAMPLE 51

The following compound was made as described in example 50 using3-(2-thienyl)-1-propanol instead of 4-ethylbenzyl alcohol:

3-(3-(3-(2-Thienyl)propoxy)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane fumarate. (Compound 110). M.p. 117°-121° C.

EXAMPLE 52 (5S,6S)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (+)L-tartrate

To a solution of (±)exo6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane(Compound 30) (28.3 g, 0.1 mol) in a 1:1 mixture of ethanol and ethylacetate (2.165 l, 50 ml/g) (+)L-tartaric acid (15.0 g, 0.1 mol) wasadded, and the mixture heated until a clear solution was obtained. Aftercooling at 4° C. overnight, the precipitated crystals were filteredgiving 19.5 g of crude material enriched with (-)exo6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane(+)L-tartrate. The mother liquor was evaporated at reduced pressuregiving 23.8 g of crude material enriched with (+)exo6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane(+)L-tartrate. This material was dissolved in a 1:1 mixture ofethanol/ethyl acetate (1.19 l, 50 ml/g) and heated at reflux. Aftercooling at 4° C. overnight the precipitated crystals were filtered off.The mother liquor was evaporated and recrystallized from a ethanol/ethylacetate mixture (50 ml/g). The title compound finally crystallized fromthe ethanol/ethyl acetate solvent mixture (50 ml/g) in 4.97 g yield.(Compound 111). M.p. 128°-129° C. α!_(D) =+28.9° (oxalate salt, MeOH).α!_(D) =÷3.71° (free base, MeOH).

EXAMPLE 53 (5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (-)D-tartrate

This compound was made in exactly the same manner as described inexample 52 using (-)D-tartaric acid (Compound 112). M.p. 128°-130° C.α!_(D) =-27.5° (oxalate salt, MeOH). α!_(D) =+3.75° (free base, MeOH).

EXAMPLE 54 (5R,6R)-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (+)L-tartrate

To a solution of(±)-exo-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane(Compound 58) (4.50 g, 17.6 mmol) in water/ethanol (20:80, 180 ml) wasadded (+)L-tartaric acid (2.64 g, 17.6 mmol). Ether (90 ml) was addedand the mixture was cooled at 4° C. overnight. The precipitated crystalswere collected by filtration. Recrystallization twice fromethanol/water/ether (10:40:50) gave the title compound in 1.5 g yield.(Compound 113). M.p. 163°-165° C. α!_(D) =+4.4° (free base, MeOH).

EXAMPLE 55 (5S,6S)-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (-)D-tartrate

This compound was made in exactly the same manner as described inexample 54 using (-)D-tartaric acid. (Compound 114). M.p. 164°-165° C.α!_(D) =-4.2° (free base, MeOH).

EXAMPLE 56 Exo-6-(3-butylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

An acidic solution of exo6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane(Compound 30) (2.5 g, 0.0088 mol) in H₂ O (20 ml+9 ml 1N HCl) was cooledin an ice-water bath as oxone (8 g, 0.13 mol) in H₂ O (40 ml) was addeddropwise. Cooling was removed and after stirring overnight the reactionwas again cooled and the pH adjusted to 9. The mixture was extractedwith CHCl₃ (3×30 ml), the extracts dried, and the solvent evaporated.The residue was suspended in EtOAc (100 ml) and extracted with saturatedaqueous K₂ CO₃ (15 ml), brine, the solvent dried and evaporated to givea yellow oil (2.6 g). The oxalate salt crystallized from EtOAc. M.p.107°-108° C. (Compound 115). Analysis C₁₃ H₂₁,N₃ O₂ S₂ --C₂ H₂ O₄,C,H,N; Theory C, 44.43; H, 5.72; N, 10.36 Found C, 44.67; H, 5.70; N,10.38.

Exo-6-(3-(2,2,3,3,4,4,4-heptafluorobutyloxy)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

A suspension of NaH (0.11 g 60% NaH in oil, 0.0028 mol) in THF (15 ml)was cooled to 11° C. as 2,2,3,3,4,4,4-heptafluorobutanol (0.56 g, 0.0074mol) was added dropwise. After gas evolution ceased, a solution of thefree base of (Compound 115) (0.8 g, 0.00254 mol) in THF (25 ml) wasadded and the reaction warmed to 35°-45° C. for 1.25 h subsequentlystirred at ambient overnight and then heated to reflux for 4 h. Anothersolution of sodium heptafluorobutoxide (0.0028 mol) prepared as abovewas added and the solution was heated to reflux 1 h. The reaction wastreated with H₂ O (10 ml), diluted with ether, and extracted with 1N HCl(2×10 ml). The acid extracts were made basic and extracted with EtOAc(3×25 ml). The organic extracts were dried, solvent evaporated andresidue purified by radial chromatography (2.5% EtOH-0.25% NH₄OH--CHCl₃) to give a yellow oil (0.48 g). The oxalate salt crystallizedfrom EtOAc to give a white solid. (Compound 116). M.p. 115°-116° C.

Analysis C₁₃ H₁₄ F₇ N₃ OS--C₂ H₂ O₄, C,H,N; Theory C, 37.27; H, 3.34; N,8.69; Found C, 37.55; H, 3.49; N, 8.80.

The following compounds were made in the same manner as described aboveusing the indicated alcohol instead of 2,2,3,3,4,4,4-heptafluorobutanol:

Exo-6-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate, (Compound 117) using methanol. M.p. 143°-145° C.

Exo-6-(3-ethoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate, (Compound 118) using ethanol. M.p. 90°-92° C.

Exo-6-(3-propoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate, (Compound 119) using propanol. M.p. 152°-154° C.

Exo-6-(3-butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate, (Compound 120) using butanol.

Exo-6-(3-pentyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate, (Compound 121) using pentanol. M.p. 109°-110° C.

Exo-6-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate, (Compound 122) using hexanol. M.p. 109°-111° C.

Exo-6-(3-isohexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octanedioxalate, (Compound 123) using isohexanol. M.p. 94°-96° C.

Exo-6-(3-(2-butynyloxy)-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate, (Compound 124) using 2-butyn-1-ol. M.p. 119°-121° C.

EXAMPLE 57Exo-6-(3-(3-(2-thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

A solution of 6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (mixture of exo- and endo-isomers (200 mg, 0.9 mmol)) inDMF (10 ml) was cooled to 5° C. whereupon potassium carbonate (180 mg,1.3 mmol) and sodium hydrosulfide monohydrate (71 mg, 1.0 mmol) wereadded to the reaction. Stirred for 1 h then potassium carbonate (120 mg,0.9 mmol) and a solution of 3-(2-thienyl)-1-chloropropane (154 mg, 1.0mmol) in DMF (5 ml) were added to the reaction and stirred for 1 h atroom temperature. The reaction was quenched with water then extractedwith ethyl acetate (3×75 ml). The organic phase was dried over NaCl/Na₂SO₄ then evaporated. The residue was purified by radial chromatographyeluting with 1% NH₄ OH/10% EtOH in CHCl₃. The exo-isomer was isolatedand the oxalate salt made to yield 29 mg of the title compound.(Compound 125). M.p. 157°-160° C.

The following compounds were made in exactly the same manner using theappropriate starting material:

Exo-6-(3-(4-fluorobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 141) using 4-fluorobenzylbromide. M.p.152.5°-153.5° C.

Exo-6-(3-(4-chlorobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 142) using 4-Chlorobenzylbromide. M.p.168°-170° C.

Exo-6-(3-(4-methylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 143) using 4-methylbenzylbromide. M.p.176.5°-178° C.

Exo-6-(3-(4-trifluoromethoxybenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 144) using4-trifluoromethoxybenzylbromide. M.p. 175°-176.5° C.

Exo-6-(3-(4-thiocarbamylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 145) using 4-thiocarbamylbenzylbromide.M.p. 125° C. dec.

Exo-6-(3-(4-methylsulfonylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 146) using 4-methylsulfonylbenzylbromide.M.p. 125° C. dec.

Exo-6-(3-(5,5,5-trifluoropentylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 147) using 5,5,5-trifluoropentylbromide.M.p. 125°-127° C.

Exo-6-(3-(3,3,3-trifluoropropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 148) using 3,3,3-trifluoropropylbromide.M.p. 93°-96° C.

Endo-6-(3-(3-(2-thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octaneoxalate

The endo-isomer was isolated from the above residue in the same manneras described for the exo-isomer. (Compound 126). M.p. 125°-128° C.

Endo-6-(3-(4,4,4-trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 127) was made in the same manner asdescribed above using 4,4,4-trifluoro-1-bromobutane instead of3-(2-thienyl)-1-chloropropane. M.p. 75°-78° C.

Endo-6-(3-(6,6,6-trifluoro-1-hexylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 128) was made as described above using6,6,6-trifluoro-1-bromohexane instead of 3-(2-thienyl)-1-chloropropane.M.p. 130°-133° C.

Endo-6-(3-(4-trifluoromethoxybenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 149) using4-trifluoromethoxybenzylbromide. M.p. 150°-152.5° C.

Endo-6-(3-(4-methylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 150) using 4-methylbenzylbromide. M.p.158°-161° C.

Endo-6-(3-(4-fluorobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 151) using 4-fluorobenzylbromide. M.p.146°-150° C.

Exo-6-(3-cyclopropylmethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from cyclopropylmethylbromide. (Compound 175). M.p.200°-201° C.

Exo-6-(3-(2-(1,3-dioxalane-2-yl)-ethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 1-bromo-2-(dioxalanyl)ethane. (Compound 176).M.p. 147°-149° C.

Exo-6-(3-(4-methoxybenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 4-methoxybenzylchloride. (Compound 177). M.p.170°-171° C.

Exo-6-(3-(2-methoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 1-bromo-2-methoxyethane. (Compound 178). M.p.142°-144° C.

Exo-6-(3-(3-hydroxypropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 1-bromo-3-hydroxypropane. (Compound 179). M.p.115°-116° C.

Exo-6-(3-(4,4,4-trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 4,4,4-trifluoro-1-bromobutane. (Compound 180).M.p. 132°-134° C.

Endo-6-(3-cyclopropylmethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from cyclopropylmethylbromide. (Compound 181). M.p.152°-154° C.

Endo-6-(3-(4-methoxybenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 4-methoxybenzylchloride. (Compound 212). M.p.155°-158° C.

Endo-6-(3-(2-methoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 1-bromo-2-methoxyethane. (Compound 182). M.p.108°-112° C.

Endo-6-(3-(4-trifluoromethylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 4-trifluoromethylbenzylchloride. (Compound183). M.p. 154°-156° C.

5-(3-(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from5-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane and4-cyanobenzylchloride. (Compound 172). M.p. 136°-138° C.

EXAMPLE 58(5S,6S)-6-(3-butylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

A solution of (5S,6S)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane tartrate (Compound 111) (4.4 g, 10.1 mmol) in water wastreated with saturated aqueous NaHCO₃ until basic then extracted withethyl acetate (3×100 ml). The organic phase was dried over NaCl/Na₂ SO₄then evaporated. The residue was taken up in 1N HCl.sub.(aq) and water(23 ml) and cooled to 0° C. A solution of oxone (9.2 g, 15.0 mmol) inwater (45 ml) was added dropwise to the reaction then stirred overnightat room temperature. The pH of the reaction was adjusted to 9 thenextracted with chloroform. The organic phase was dried over NaCl/Na₂ SO₄then evaporated to yield 3.9 g of free base. Crystallization with oxalicacid gave the title compound. (Compound 129). M.p. 147°-151° C.

The following compounds were made in exactly the same manner using theappropriate starting material:

(5R,6R)-6-(3-propylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 152) M.p. 160°-162° C.

(5S,6S)-6-(3-propylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!oxtane oxalate (Compound 153) M.p. 160°-162° C.

Exo-6-(3-propylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 184). M.p. 201°-203° C.

(+)3-(3-Butylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate (Compound 220) M.p. 121°-122° C., from(+)3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneoxalate.

EXAMPLE 59(5S,6S)-6-(3-(4,4,4-trifluoro-1-butylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate

A solution of(5S,6S)-6-(3-butylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (Compound 129) (1.3 g, 4.1 mmol) in DMF (20 ml) was warmedto 40° C. whereupon Na₂ S.9H₂ O (1.2 g, 5.0 mmol) was added to thereaction. The reaction was heated to 100° C. for 3 h whereupon1-bromo-4,4,4-trifluorobutane in DMF (5 ml) was added. Stirred at 100°C. for 1 h then at room temperature overnight. Poured the reaction intowater then extracted with ethyl acetate (3×100 ml). The organic phasewas dried over NaCl/Na₂ SO₄ then evaporated. The residue was purified byradial chromatography eluting with 2% NH₄ OH/20% EtOH in CHCl₃. Theoxalate salt was made to yield 545 mg of the title compound (Compound130). M.p. 147°-151° C.

In the same manner the following compounds were prepared:

(+)3-(3-(2-Butanonylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 221) M.p. 189°-191° C., starting from(+)3-(3-butylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneand 1-bromo-2-butanone.(+)3-(3-(2-Hydroxybutylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo2.2.2!octane oxalate (Compound 222), starting from(+)3-(3-butylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octaneand 1-bromo-2-hydroxybutane.

EXAMPLE 60 3-(1,2,5-Thiadiazol-3-yl)-1-azabicyclo 2.2.2!octane fumarate

To a solution of 1-butanethiol (2.2 ml, 20 mmol) in THF (50 ml) wasadded sodium hydride (50% suspension in mineral oil, 960 mg, 20 mmol) at0° C. The reaction was stirred for 1 h, whereafter a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 2.2.2!octane (830 mg,3.6 mmol) in THF (25 ml) was added. The reaction mixture was stirred atroom temperature for 2 h. Water was added and the mixture extracted withethyl acetate. The organic phase was dried and evaporated and theresidue purified by column chromatography (eluent: CH₂ Cl₂ :MeOH:NH₄ OH(80:20:0.5)). Crystallization with fumaric acid from isopropanol/ethergave the title compound in 70 mg yield (Compound 132). M.p. 177°-179° C.

EXAMPLE 61 (5S)-1-Azabicyclo 3.2.1!octan-6-one (+)camphorsulfonate

To a solution of (±)1-azabicyclo 3.2.1!octan-6-one (124 g, 1 mol) inethanol (100 ml) was added a solution of (+)camphorsulfonic acid (232 g,1.0 mol) in 200 ml ethanol. The mixture was heated to 70° C. and slowlycooled over 2 hours to 5° C. The precipitated crystals were collected byfiltration and washed with cold ethanol (3×40 ml). The crude compoundwas crystallized from ethanol (150 ml) giving the title compound in 57.3g yield. M.p. 267°-268° C. (decomp.). α!_(D) =+48° (water).

EXAMPLE 62 (5R)-1-Azabicyclo 3.2.1!octan-6-one (-)camphorsulfonate

This compound was made in exactly the same manner as described inexample 1 using (±)1-azabicyclo 3.2.1!octan-6-one and (-)camphorsulfonicacid. M.p. 267°-268° C. (decomp.) α!_(D) =-48° (water).

EXAMPLE 63

A. (5S)-Ethyl(1-azabicyclo 3.2.1!octan-6-ylidene)cyanoacetatehydrochloride

(5R)-1-Azabicyclo 3.2.1!octan-6-one (-)camphorsulfonate (61.8 g, 135.0mmol) and triethylamine (20.4 g, 202 mmol) and ethyl cyanoacetate (61.8g, 547 mmol) were mixed and stirred at room temperature for 6 days.Toluene (120 ml) and water (120 ml) were added to the reaction mixtureand the pH was adjusted to 2 with concentrated hydrochloric acid. Thephases were separated and the water phase extracted with toluene (30ml). The combined organic phases were washed with water (20 ml). Thecombined water phases were adjusted to pH=9.4 with NH₃ (25% in water)and extracted with toluene (1×120 ml, 1×60 ml). The combined tolueneextracts were evaporated. The residue was dissolved in ethanol (120 ml)and concentrated hydrochloric acid (16 ml) was added. The title compoundprecipitated in 22 g yield. Upon evaporation of the mother liquor andcrystallization from ethanol (40 ml) further 14.6 g of the titlecompound was isolated.

B. Exo- andEndo-6-chloro-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (+)L-tartrate

(5S)-Ethyl(1-azabicyclo 3.2.1!octan-6-ylidene)cyanoacetate (220 g, 1mol) was dissolved in abs. ethanol (500 ml). Palladium on carbon (10 g,5%) was added and the mixture treated with hydrogen in a Parr shaker at20 psi for 10 hours. The catalyst was filtered off, and the solutionevaporated to a final volume of 400 ml. This solution was added to asolution of sodium (25.3 g, 1.1 mol) in ethanol (200 ml). Isoamylnitrite(183.3 g, 1.56 mol) was added at 0°-5° C. The reaction mixture waswarmed to room temperature and stirred at this temperature for 6 hours.The reaction mixture was cooled to 4° C. and left at 4° C. overnight.The reaction mixture was evaporated at reduced pressure, toluene (300ml) was added and the mixture was again evaporated. The residue wasdissolved in DMF (300 ml) and slowly added to a mixture ofsulfurmonochloride (466 g, 3.5 mol) in DMF (140 ml) at 0°-5° C. Thetemperature was slowly raised to 20° C. over 3 hours and the reactionmixture was stirred at room temperature overnight. Water (750 ml) wascarefully added. The pH was adjusted to 4 by addition of sodiumhydroxidesolution (36% NaOH). The mixture was filtered at 70° C., cooled andbasified with sodiumhydroxide. The water phase was extracted withtoluene (900 ml+400 ml). The organic phases were evaporated. The residuewas dissolved in ethanol (670 ml) and (+)L-tartaric acid (117 g, 0.8mol) was added. The precipitated crystals were filtered giving the titlecompound in 270 g yield.

The following compounds were prepared in exactly the same manner:

2-Methyl-6-chloro-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane starting from 2-methyl-1-azabicyclo 3.2.1!octan-6-one.

8-Methyl-6-chloro-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane starting from 8-methyl-1-azabicyclo 3.2.1!octan-6-one.

C. (5S,6S)-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneand (5S,6R)-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octanehydrochloride 6-Chloro-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (121 g, 0.6 mol) dissolved in ethanol (1.5 l) was treatedwith Raney Nickel (20 ml, 50%) and hydrogen at atmospheric pressure. Thecatalyst was filtered and the ethanol evaporated at reduced pressure.The residue was recrystallized from ethanol (400 ml) giving the titlecompound in 115.8 g yield.

The following compounds were made in exactly the same manner:

Exo-2-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (Compound 169) andendo-2-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (Compound 170) starting fromexo/endo-2-methyl-6-chloro-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane.

Exo-8-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (Compound 171) andendo-8-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (Compound 213) starting fromexo/endo-8-methyl-6-chloro-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane.

D. (5S,6S)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (+)L-tartrate

Starting from a mixture of (5S,6S)- and(5S,6R)-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octanedescribed in example 63C, the chlorine was substituted with butylthio asdescribed in example 14. A 1:9 mixture of (5S,6S)- and(5S,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane(10 g, 35 mmol) was dissolved in toluene (40 ml) and treated withpotassium tertbutoxide (0.5 g) at reflux for 1 hour. The toluenesolution was washed with water (15 ml) dried and evaporated. The residuecrystallized with (+)L-tartaric acid giving the optical pure titlecompound in 12.5 g yield. (Compound 111). M.p. 128°-129° C.

EXAMPLE 64

Using the (5S,6S), (5R,6R), (5S,6R) and (5R,6S) enantiomers of6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane (examples61, 62 and 63) obtained from resolved (5S)-1-azabicyclo3.2.1!octan-6-one (example 61) or (5R)-1-azabicyclo 3.2.1!octan-6-one(example 62) the following compounds were synthesized using theappropriate alkylhalogenide and separating exo- and endo compounds bycolumn chromatography:

(5R,6R)-6-(3-(4-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 154) using 4-cyanobenzylbromide. M.p.196°-197° C.

(5S, 6S)-6-(3-(4-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1 !octane oxalate (Compound 155) using 4-cyanobenzylbromide. M.p.195°-196° C.

(5S,6R)-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane(+)L-tartrate (Compound 156) using propylbromide.

(5R,6R)-6-(3-isohexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (+)L-tartrate (Compound 157) using isohexylbromide. M.p.152°-153° C.

(5S,6S)-6-(3-isohexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 158) using isohexylbromide. M.p.118°-122° C.

(5R,6S)-6-(3-isohexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (+)L-tartrate (Compound 159) using isohexylbromide. M.p.102°-103° C.

(5S,6R)-6-(3-(4,4,4-trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (-)D-tartrate (Compound 160) using4,4,4-trifluorobutylbromide. M.p. 94°-96° C.

(5R,6S)-6-(3-(4,4,4-trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane (+)L-tartrate (Compound 161) using4,4,4-trifluorobutylbromide. M.p. 94°-96° C.

(5S,6R)-6-(3-(4-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 162) using 4-cyanobenzylbromide. M.p.167°-172° C.

(5R,6S)-6-(3-(4-cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 163) using 4-cyanobenzylbromide. M.p.168°-172° C.

(5R,6S)-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate (Compound 164) using propylbromide. M.p. 64°-65° C.

(5R,6R)-6-(3-(3,3,3-trifluoropropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane hydrochloride (Compound 165) using3,3,3-trifluoropropylbromide. M.p. 199°-202° C.

(5R,6R)-6-(3-(3-(2-thionyl)propylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octaneoxalate (Compound 166) using 3-(2-thienyl)propylchloride. M.p. 135°-139°C.

(5R,6R)-6-(3-(4,4,4-trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 167) using 4,4,4-trifluorobutylbromide.M.p. 153°-154° C.

(5R,6S)-6-(3-(3,3,3-trifluoropropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane hydrochloride (Compound 168) using3,3,3-trifluoropropylbromide. M.p. 170°-174° C.

(+)-Exo-6-(3-methylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 185). M.p. 144°-145° C.

(+)-Exo-6-(3-ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 186). M.p. 120°-124° C.

(+)-Exo-6-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 187). M.p. 128°-129° C.

(+)-Exo-6-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 188). M.p. 149°-150° C.

(-)-Exo-6-(3-methylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 189). M.p. 144°-145° C.

(-)-Exo-6-(3-ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 190). M.p. 120°-123° C.

(-)-Exo-6-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 191). M.p. 132°-1340C.

(-)-Exo-6-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 192). M.p. 149°-150° C.

(+)-Endo-6-(3-methylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate. (Compound 193). M.p. 138°-139° C.

(+)-Endo-6-(3-ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 194). M.p. 87°-89° C.

(+)-Endo-6-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate. (Compound 195). M.p. 65°-70° C.

(+)-Endo-6-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 196). M.p. 89°-90° C.

(-)-Endo-6-(3-methylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate. (Compound 197). M.p. 137°-140° C.

(-)-Endo-6-(3-ethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 198). M.p. 107°-110° C.

(-)-Endo-6-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate. (Compound 199). M.p. 85°-90° C.

(-)-Endo-6-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octaneoxalate. (Compound 200). M.p. 132°-134° C.

(+)-Exo-6-(3-(4-trifluoromethylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 4-trifluoromethylbenzylchloride. (Compound201). M.p. 172°-174° C.

(+)-Exo-6-(3-(4-nitrobenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 4-nitrobenzylchloride. (Compound 202). M.p.173°-174° C.

(+)-Exo-6-(3-(2-hydroxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate from 2-hydroxy-1-chloroethane. (Compound 203). M.p.179°-181° C.

(+)-Exo-6-(3-(2-propanonylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 228) using 1-bromo-2-propanone. M.p.151°-154° C.

(+)-Exo-6-(3-(2-hydroxypropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 229) using 1-bromo-2-hydroxypropane. M.p.179°-180° C.

(+)-Exo-6-(3-(3-phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 230) using 1-bromo-3-phenylpropane. M.p.135°-136° C.

(-)-Exo-6-(3-(3-phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 231) using 1-bromo-3-phenylpropane. M.p.135°-136° C.

(+)-Endo-6-(3-(3-phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 232) using 1-bromo-3-phenylpropane. M.p.110°-113° C.

(-)-Endo-6-(3-(3-phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1 !octane oxalate (Compound 233) using 1-bromo-3-phenylpropane. M.p.100°-106° C.

(+)-Exo-6-(3-(4-fluorophenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 234) using1-bromo-2-(4-fluorophenoxy)ethane.

(-)-Exo-6-(3-(4-fluorophenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 235) using1-bromo-2-(4-fluorophenoxy)ethane. M.p. 132°-137° C.

(+)-Endo-6-(3-(4-fluorophenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1azabicyclo3.2.1!octane oxalate (Compound 236) using1-bromo-2-(4-fluorophenoxy)ethane.

(-)-Endo-6-(3-(4-fluorophenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate (Compound 237) using1-bromo-2-(4-fluorophenoxy)ethane. M.p. 144°-147° C.

In the above examples optical rotation is measured on the free base.

EXAMPLE 65

The following compounds were prepared in exactly the same manner asdescribed in example 64:

Endo-2-methyl-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromendo-2-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane. (Compound 204). M.p. 123°-124° C.

Endo-8-methyl-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromendo-8-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane. (Compound 205). M.p. 172°-175° C.

Exo-2-methyl-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-2-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane. (Compound 206). M.p. 155°-156° C.

Exo-8-methyl-6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-8-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane. (Compound 207). M.p. 144°-146° C.

Exo-2-methyl-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-2-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane. (Compound 208). M.p, 160°-164° C.

Exo-8-methyl-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-8-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane. (Compound 209). M.p. 143°-147° C.

Exo-2-methyl-6-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-2-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane. (Compound 210). M.p. 128°-131° C.

Exo-8-methyl-6-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane oxalate fromexo-8-methyl-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane. (Compound 211). M.p. 140°-142° C.

We claim:
 1. A method of treating a urinary bladder dysfunction in asubject in need thereof comprising administering to the subject aneffective amount of a compound of formula I ##STR9## wherein X is oxygenor sulphur;R is hydrogen, amino, halogen, --CHO, --NO₂, --R⁴, --Y,--NHCO--R⁴, --OR⁴, --SR⁴, --SOR⁴, --SO₂ R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₀-cycloalkenyl, C₄₋₁₀ -(cycloalkylalkyl), --Z¹ --C₃₋₁₀ -cycloalkyl, --Z¹--C₄₋₁₀ -cycloalkenyl, --Z¹ --C₄₋₁₀ -(cycloalkylalkyl), --Z¹ --C₄₋₁₀-(cycloalkenylalkyl), --Z¹ --C₄₋₁₀ -(methylenecycloalkylalkyl),--NH--R⁴, --NR⁴ R⁵, --NH--OR⁴, --CH═NOR⁴, or an aromatic ring selectedfrom the group consisting of phenyl, benzyloxycarbonyl, phenoxy,benzoyl, tetrahydronaphthyl, naphtyl, and indenyl, wherein each aromaticring is optionally substituted with halogen, --NO₂, --CN, C₁₋₄ -alkyl,C₁₋₄ -alkoxy, --OCF₃, --CONH₂, --CSNH₂, phenoxy or phenyl; or R is --Z¹--R⁶ --Z² --R⁵, --Z¹ --R⁶ --Z² --R⁷ --Z³ --R⁵, --Z¹ --CO--R⁵, --Z¹ --R⁶--CO--R⁵, --Z¹ --R⁶ --CO₂ --R⁵, --Z¹ --R⁶ --O₂ C--R⁵, --Z¹ --R⁶--COHN--R⁵, --Z¹ --R⁶ --NHCO--R⁵, --Z¹ --R⁶ --Y, --Z¹ --R⁶ --Z² --Y,wherein Z¹ and Z² independently are oxygen or sulphur, and R⁴ and R⁵independently are straight or branched C₁₋₁₅ -alkyl, straight orbranched C₂₋₁₅ -alkenyl, straight or branched C₂₋₁₅ -alkynyl, each ofwhich is optionally substituted with one or more halogen(s), C₁₋₆-alkoxy, --CF₃, --CN, --COOH, --OH, --NH₂, C₁₋₆ -alkyl ester, --SH,--NHR⁴, --NR⁴ R⁵, or a phenyl or phenoxy group, wherein the phenyl orphenoxy group is optionally substituted with halogen, --NO₂, --CN, C₁₋₄-alkyl, C₁₋₄ -alkoxy, --OCF₃, --CONH₂, --CSNH₂, phenyl or phenoxy, andwherein R⁶ and R⁷ independently are straight or branched C₁₋₁₀-alkylene, straight or branched C₂₋₁₀ -alkenylene, straight or branchedC₂₋₁₀ -alkynylene, each of which is optionally substituted with one ormore halogen(s), --CF₃, --CN, --COOH, --OH, --NH₂, C₁₋₆ -alkyl ester,--SH, --NHR⁴, --NR⁴ R⁵, phenyl or phenoxy, and Y is a heterocyclic groupselected from the group consisting of thienyl, tetrazolyl, thiadiazolyl,benzothiazolyl, phthalimido, pyridyl and 1,3-dioxolanyl wherein theheterocyclic group is optionally substituted at carbon or nitrogenatom(s) with straight or branched C₁₋₆ -alkyl, phenyl or benzyl, or acarbon atom of the heterocyclic group together with an oxygen atom toform a carbonyl group, or wherein the heterocyclic group is optionallyfused with a phenyl group; and G is an azabicyclic ring of formula II##STR10## wherein the thiadiazole or oxadiazole ring is attached to anycarbon atom of the azabicyclic ring;R¹ and R² may be present at anyappropriate position of the thiadiazole or oxadiazole ring andindependently are hydrogen, straight or branched C₁₋₅ -alkyl, straightor branched C₂₋₅ -alkenyl, straight or branched C₂₋₅ -alkynyl, straightor branched C₁₋₁₀ -alkoxy, --OH, halogen, --NH₂, carboxy or straight orbranched C₁₋₅ -alkyl substituted with --OH; m and n are 2; p is 1; and..... is a single or double bond; ora pharmaceutically acceptable saltthereof.
 2. The method according to claim 1, wherein X is S.
 3. Themethod according to claim 1, wherein R¹ and R² independently arehydrogen, methyl, methoxy, hydroxy, halogen or amino.
 4. The methodaccording to claim 1, wherein R¹ and R² are hydrogen.
 5. The methodaccording to claim 4, wherein R⁴ is straight or branched C₁₋₁₅ -alkyl.6. The method according to claim 4, wherein R⁴ is branched C₄₋₁₅ -alkyl.7. The method according to claim 4, wherein R⁴ is straight C₃₋₅ -alkyl.8. The method according to claim 1, wherein the compound is selectedfrom thefollowing:4-Chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene;4-Chloro-3-(3-propyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene4-Chloro-3-(3-pentyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene;4-Chloro-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene; 4-Chloro-3-(1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene;4-Chloro-3-(3-butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene;4-Chloro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene; 3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene; 3-(3-Methoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene; 3-(3-Propoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene; 3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.3.1!non-3-ene; ora pharmaceutically acceptable salt thereof.